Mohamed Z. Alimohamed, Lennart F. Johansson, Ludolf G. Boven, Krista van Dijk, Paul van der Zwaag, Richard J. Sinke, Rolf H. Sijmons, Birgit Sikkema-Raddatz, Jan D H Jongbloed
Departments of Genetics, University Medical Center Groningen, Groningen, The Netherlands
Next generation sequencing is increasingly used for clinical evaluation of patients with cardiomyopathies because it allows for simultaneous evaluation of multiple genes known to be associated with the disease. However, the diagnostic yield is variable in routine clinical practice. Furthermore, analysis of copy number variations is still not routinely performed.
(1) To determine the diagnostic yield of our custom targeted NGS gene panel used in routine clinical diagnostics in a Dutch cohort of over 2000 cardiomyopathy patients. (2) Examine the impact on the yield of analyzing this cohort for single or multiple exon duplications and deletions.
Up to 61 genes known to be implicated in cardiomyopathies were selected for enrichment and analysis on DNA isolated from peripheral blood from patients as a routine procedure. Patients directed for genetic testing to our clinical genetics laboratory having a referral diagnosis for various types of cardiomyopathies were included in this study [N=2002]. A written informed consent was obtained for all patients referred to our clinical genetics laboratory. Classification of variants was based on guidelines for variant interpretation recommended by the American College of Medical Genetics and Genomics. Diagnostic yield was calculated using cases where a likely pathogenic or pathogenic variant was detected. Putative exonic deletions/duplications were analyzed using CoNVaDING and XHMM tools using settings previously described.
Results and Conclusion:
An overall diagnostic yield of 23% was achieved. CNVs were detected in 16 patients. Variants of unknown clinical significance were identified in 39% patients. These results illustrate the need to further reassess disease variant classification.
Cardiomyopathy, NGS-panel, Diagnostic-yield